ES2663614T3 - Process for preparing 3,5-bis (haloalkyl) pyrazole derivatives from alpha, alpha-dihaloamines and ketimines - Google Patents

Abstract

Preparation process of 3,5-bis (haloalkyl) pyrazoles of formula (Ia) and (Ib) ** (See formula) ** in which R1 and R3 are each independently selected from C1-C6 haloalkyl; R2 is selected from H, halogen, COOH, (C> = O) OR5, CN and (C> = O) NR6R7; R4 is selected from H, C1-C8 alkyl, CH2COO C1-C8 alkyl, aryl, pyridyl; R5 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl, and C7-C19 alkylaryl; R6 and R7 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl or in which R6 and R7 together with the nitrogen atom to which they are attached they can form a four, five or six membered ring characterized in that in step (A), α, α-dihaloamines of formula (II), ** (See formula) ** in which R1 is as defined above; X is independently selected from F, Cl, or Br, R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl, and C7-C19 alkylaryl or where R10 and R11 together with the nitrogen atom to which they are attached they can form a five or six membered ring; are reacted with compounds of formula (III), ** (See formula) ** in which R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7 alkylaryl -C19-, OR9; R9 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl, C7-C19 alkylaryl; R2 and R3 are as defined above; to form the compound of formula (V): (V-1), (V-2), (V-3), (V-4) and (V-5) ** (See formula) ** and because in step (B) in the presence of hydrazine H2N-NHR4 (IV) - R4 being as defined above - a cyclization of (V) is carried out to form (Ia / Ib).

Description

DESCRIPTION

Process for preparing 3,5-bis (haloalkyl) pyrazole derivatives from alpha, alpha-dihaloamines and ketimines

The present invention relates to a new process for preparing 3,5-bis (haloalkyl) pyrazol 5 derivatives from a, a-dihaloamines and ketimines.

Derivatives of polyfluoroalkylpyrazolylcarboxylic acid and 3,5-bis (haloalkyl) pyrazoles are valuable precursors of fungicidal active ingredients (WO 2003/070705, WO 2008/013925, WO 2012/025557).

Generally, pyrazolecarboxylic acid derivatives are prepared by reacting acrylic acid derivatives having two leaving groups with hydrazines (WO 2009/112157 and WO 2009/106230). WO 2005/042468 10 discloses a process for the preparation of 2-dihaloacyl-3-aminoacrylic esters by the reaction of acid halides with dialkylaminoacrylic esters and subsequent cyclization thereof with alkyl hydrazines. WO 2008/022777 describes a process for preparing derivatives of 3-dihalomethylpyrazol-4-carboxylic acid by reacting a, a-difluoroamines in the presence of Lewis acids with derivatives of acrylic acid and subsequent reaction thereof with alkyl hydrazines . WO 2013/113829 discloses the preparation 15 of derivatives of 3,5-bis (fluoroalkyl) pyrazol-4-carboxylic acid by the reaction of a-dihaloamines with derivatives of p-keto carboxylic acid and the subsequent reaction of the resulting product with hydrazines.

The preparation of fluorinated pyrazoles by the addition of phenylhydrazine to 2-fluoro-1,3-diketones is known from J. C. Sloop et al., J. Fluor. Chem. 2002, 118, 135-147.

3,5-bis (fluoroalkyl) pyrazoles are prepared by the reaction of the diketone bisperfluoroalkyl (for example, 1,1,1,5,5,5-hexafluoroacetylacetone) with hydrazines (cf. Pashkevich et al., Zhurnal Vsesoyuznogo Khimicheskogo Obshchestva im. DI Mendeleeva (1981), 26 (1), 105-7), the yield being only 27-40%. The synthesis, isolation and purification of the diketone polyfluoroalkyl is very complex since the compounds are generally very volatile and highly toxic. In the light of the prior art described above, it is an object of the present invention to provide a process that does not have the aforementioned disadvantages and therefore gives a route for 3,5-bis (haloalkyl) pyrazole 3,5 derivatives. -bis (haloalkyl) with high yields.

The object described above is achieved by a process of preparing 3,5-bis (haloalkyl) pyrazoles of the formula (la) and (Ib),

image 1

in which

R1 and R3 are each independently selected from C1-C6 haloalkyl;

R2 is selected from H, halogen, COOH, (C = O) OR5, CN and (C = O) NR6R7;

R4 is selected from H, C1-C8 alkyl, CH2COO-C1-C8 alkyl, aryl, pyridyl;

R5 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl;

R6 and R7 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl or wherein

R6 and R7 together with the nitrogen atom to which they bind can form a four, five or six member ring characterized in that in step (A), a, a-dihaloamines of the formula (II),

image2

in which

R1 is as defined above;

X is independently selected from F, Cl or Br,

R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, Ca-C ^ aryl,

C7-C19 arylalkyl and C7-C19 alkylaryl or where

R10 and R11 together with the nitrogen atom to which they bind can form a five or six member ring; they are reacted with the compounds of the formula (III),

image3

10 in which

R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl, OR9; R9 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl, C7-C19 alkylaryl;

R2 and R3 are as defined above;

to form the compound of formula (V): (V-1), (V-2), (V-3), (V-4) and (V-5)

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image4

and that in step (B) in the presence of H2N-NHR4 (IV) hydrazine - with R4 being as defined above - a cyclization of (V) is carried out to form (la / Ib).

A process according to the invention is preferred, wherein the radicals in the formula (la), (Ib), (II), (III), (IV) and (V) are defined as follows:

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R1 and R3 are each independently selected from difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2 -difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, tetrafluoroethyl (CF3CFH), pentafluoroethyl and 1,1,1-trifluoroprop-2-yl;

R2 is selected from H, F, Cl, Br, COOCH3, COOC2H5, COOC3H7, CN and CON (CH3) 2, CON ^ Hsfe R4 is selected from H, C1-C8 alkyl, CH2COO-C1-C8 alkyl, phenyl, pyridyl;

R8 are each independently selected from methyl, ethyl, n-, / so-propyl, n-, / so-, sec- and f-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, C7- alkylaryl C19, tolyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl;

X is independently selected from F or Cl;

R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C7-C19 arylalkyl or

R10 and R11 together with the nitrogen atom to which they bind can form a five-member ring.

More preferred is a process according to the invention, where the radicals in the formula (la), (Ib), (II), (III), (IV) and (V) are defined as follows:

R1 and R3 are each independently selected from trifluoromethyl, difluoromethyl, difluorochloromethyl, pentafluoroethyl;

R2 is selected from H, Cl, CN, COOC2H5;

R4 is selected from H, methyl, ethyl, n-, isopropyl, n-, / so-, sec- and f-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, phenyl, CH2COOCH3, CH2COOCH2CH3;

R8 is selected from methyl, ethyl, n-, / so-propyl, n-, iso-, sec- and f-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, C7-C19 alkylaryl;

X is independently selected from F or Cl;

R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl.

Even more preferred is a process according to the invention, where the radicals in the formula (Ia), (Ib), (II), (III), (IV) and (V) are defined as follows:

R1 and R3 are each independently selected from CF2H and CF3;

R2 is selected from H or COOC2H5;

R4 is selected from H, methyl, ethyl, CH2COOCH3, CH2COOCH2CH3, phenyl;

R8 is selected from ethyl, n-, / so-propyl, n-, cyclopentyl, cyclohexyl, benzyl;

X is F;

R10 and R11 are each independently selected from C1-C12-alkyl.

More preferred is a process according to the invention, wherein the radicals in the formula (Ia), (Ib), (II), (III), (IV) and (V) are defined as follows:

R1 and R3 are CF2H;

R2 is H;

R4 is selected from H, methyl, CH2COOCH2CH3, phenyl;

R8 is selected from / so-propyl and benzyl;

X is F;

R10 and R11 are each independently selected from methyl and ethyl.

Surprisingly, the pyrazoles of the formula (I) can be prepared under the conditions of the invention in good yields and with high purity, which means that the process according to the invention overcomes the above-mentioned disadvantages of the preparation procedures described previously. in the prior art.

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A further aspect of the present invention are the compounds of formula (IlI-a):

image5

in which

R3a is HCF2;

R2, R8, R9 are as defined above.

Compounds of formula (IlI-a) in which R3a is HCF2 are preferred;

R2 is H;

R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, benzyl.

More preferred are the compounds of formula (III-a) in which

R3a is HCF2;

R2 is H;

R8 is selected from iso-propyl, benzyl.

A further aspect of the present invention are the compounds of formula (V-1):

image6

in which the radicals are as defined above.

Compounds of formula (V-1) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl and benzyl;

R10 and R11 are each independently selected from C1-C5 alkyl;

A "is BF4".

More preferred are the compounds of formula (V-1) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from iso-propyl and benzyl;

R and R are each independently selected from methyl and ethyl;

A 'is BF4 ".

A further aspect of the present invention are the compounds of formula (V-2):

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image7

in which the radicals are as defined above.

Compounds of formula (V-2) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl and benzyl.

More preferred are the compounds of formula (V-2) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from iso-propyl and benzyl.

A further aspect of the present invention are the compounds of formula (V-3):

image8

in which the radicals are as defined above.

Compounds of formula (V-3) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from C1-12 alkyl, C3-8 cycloalkyl and benzyl;

R and R are each independently selected from

More preferred are the compounds of formula (V-3) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from iso-propyl and benzyl;

R10 and R11 are each independently selected from

A further aspect of the present invention are the compounds of formula (V-4):

image9

in which the radicals are as defined above.

C1-5 alkyl.

methyl and ethyl.

Compounds of formula (V-4) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from C1-12 alkyl, C3-8 cycloalkyl and benzyl.

More preferred are the compounds of formula (V-4) in which

R1 and R3 are HCF2;

R2 is H;

R8 is selected from iso-propyl and benzyl.

A further aspect of the present invention are the compounds of formula (V-5):

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in which

R1 and R3 are each independently selected from HCF2, CF3, CF2Cl;

R2 is H.

General Definitions

In the context of the present invention, the term "halogen" (Hal), unless otherwise defined, comprises those elements that are selected from the group comprising fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

Optionally, the substituted groups may be mono- or polysubstituted, where the substituents in the case of polysubstitutions may be the same or different.

20 Haloalkyl: straight or branched chain alkyl groups having 1 to 6 and preferably 1 to 3 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups can be replaced by halogen atoms such as specified above, for example (but not limited to) C1-C3 haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-bromoethyl 225 fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro, 2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichlorethyl , pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a substituent of composite material, for example, haloalkylaminoalkyl etc., unless defined elsewhere. Preference is given to alkyl groups substituted by one or more halogen atoms, for example, trifluoromethyl (CF3), difluoromethyl (CHF2), CF3CH2, CF2Cl or CF3CCl2.

The alkyl groups in the context of the present invention, unless otherwise defined, are saturated linear, branched or cyclic hydrocarbyl groups. The definition of C1-C12 alkyl encompasses the broadest range defined herein for an alkyl group. Specifically, this definition encompasses, for example, the meanings of methyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3, 3- dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.

The alkenyl groups in the context of the present invention, unless otherwise defined, are linear, branched or cyclic hydrocarbyl groups containing at least a single unsaturation (double bond). The definition C2-C12 alkenyl encompasses the broadest range defined herein for an alkenyl group. Specifically, this definition covers, for example, the meanings of vinyl; allyl (2-propenyl), isopropenyl (1- methyletenyl); but-1-enyl (crotyl), but-2-enyl, but-3-enyl; hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl;

Hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl; oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, oct-7-enyl; non-1-enyl, non-2-enyl, non-3-enyl, non-4-enyl, non-5-enyl, non-6- enyl, non-7-enyl, non-8-enyl; dec-1-enyl, dec-2-enyl, dec-3-enyl, dec 4-enyl, dec-5-enyl, dec-6-enyl, dec-7- enyl, dec-8-enyl, dec-9 -enyl; undec-1-enyl, undec-2-enyl, undec-3-enyl, undec-4-enyl, undec-5-enyl, undec-6- enyl, undec-7-enyl, undec-8-enyl, undec- 9-enyl, undec-10-enyl; dodec-1-enyl, dodec-2-enyl, dodec-3-enyl,

45 dodec-4-enyl, dodec-5-enyl, dodec-6-enyl, dodec-7-enyl, dodec-8-enyl, dodec 9-enyl, dodec-10-enyl, dodec-11-enyl; Buta-1,3-dienyl or penta-1,3-dienyl.

image10

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Alkynyl groups in the context of the present invention, unless otherwise defined, are linear, branched or cyclic hydrocarbyl groups containing at least one double unsaturation (triple bond). The C2-C12 alkynyl definition encompasses the broadest range defined herein for an alkynyl group. Specifically, this definition encompasses, for example, the meanings of ethynyl (acetylenyl); prop-1-inyl and prop-2- inyl.

Cycloalkyl: saturated, monocyclic hydrocarbyl groups having 3 to 8 and preferably 3 to 6 ring carbon members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a substituent of composite material, for example, cycloalkylalkyl etc., unless defined elsewhere.

Aryl groups in the context of the present invention, unless otherwise defined, are aromatic hydrocarbyl groups that may have one, two or more heteroatoms selected from O, N, P and S. The aryl definition Ca-18 encompasses the broadest range defined in this document for an aryl group having 5 to 18 skeleton atoms, where carbon atoms can be exchanged for heteroatoms. Specifically, this definition encompasses, for example, the meanings of phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl; 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol 3 -yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3- yl , 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl; 1-pyrrolyl, 1-pyrazolyl,

1.2.4-triazol-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl; 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.

The arylalkyl groups (aralkyl groups) in the context of the present invention, unless otherwise defined, are alkyl groups that are substituted with aryl groups, can have a C1-8 alkylene chain and can have, in the aryl skeleton , one or more heteroatoms selected from O, N, P and S. The definition of the C7-19 aralkyl group encompasses the broadest range defined herein for an arylalkyl group having a total of 7 to 19 atoms in the skeleton chain and alkylene Specifically, this definition encompasses, for example, the meanings of benzyl and phenylethyl.

Alkylaryl groups (alkaryl groups) in the context of the present invention, unless otherwise defined, are aryl groups that are substituted with alkyl groups, may have a C1-8 alkylene chain and may have, in the aryl skeleton, one or more heteroatoms selected from O, N, P and S. The definition of the C7-19 alkylaryl group encompasses the broadest range defined herein for a alkylaryl group having a total of 7 to 19 atoms in the skeleton and alkylene chain . Specifically, this definition covers, for example, the meanings of tolyl or 2,3-,

2.4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl.

The intermediate term used in the context of the present invention describes the substances that are produced in the process according to the invention and are prepared for further chemical processing and are consumed or used therein in order to be converted into another substance. Intermediates can often be isolated and stored intermediate or used without prior isolation in the subsequent reaction stage. The term "intermediate" also encompasses generally unstable and short-lived intermediates that occur transiently in multi-stage reactions (reaction stages) and to which the local minimums in the reaction energy profile can be assigned.

The compounds of the invention may be present as mixtures of any of the different possible isomeric forms, especially of stereoisomers, for example, E and Z, threo and erythro isomers, and optical isomers, but also tautomers. Both E and Z isomers are described and claimed, as are threo and erythro isomers, as well as optical isomers, any mixture of these isomers, and also possible tautomeric forms.

Procedure description

The procedure is illustrated in Scheme 1:

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Scheme 1:

image11

Stage (A)

In step (A), a, a-dihaloamines of the formula (II) are first reacted, in the presence of a Lewis acid [L], with compounds of the formula (III).

Compounds of the general formula (II) are preferred are 1,1,2,2-tetrafluoroethyl-N, N-dimethylamine (TFEDMA), 1,1,2,2-tetrafluoroethyl-N, N-diethylamine, 1,1 , 2-Trifluoro-2- (trifluoromethyl) ethyl-N, N-dimethylamine, 1,1,2-trifluoro-2- (trifluoromethyl) ethyl-N, N-diethylamine (Ishikawa reagent), 1,1,2- trifluoro-2-chloroethyl-N, N-dimethylamine and 1,1,2-trifluoro-2- chloroethyl-N, N-diethylamine (Yarovenko reagent).

The compounds of the general formula (II) are used as iminoalkylating agents. Preference is given to 1,1,2,2-tetrafluoroethyl-N, N-dimethylamine (TFEDMA) and 1,1,2,2-tetrafluoroethyl-N, N-diethylamine, and particularly preference to 1,1,2,2 - tetrafluoroethyl-N, N-dimethylamine. a, a-Dihaloamines such as TFEDMA and Ishikawa reagent are commercially available or can be prepared (cf. Yarovenko et al., Zh. Obshch. Khim. 1959, 29, 2159, Chem. Abstr. 1960, 54, 9724h or Petrov et al., J. Fluor. Chem. 109 (2011) 25-31).

Yagupolskii et al. (Zh. Organicheskoi Khim. (1978), 14 (12), 2493-6) shows that the reaction of Yarovenko reagent (FClCHCF2NEt2) with nitriles of the formula RCH2CN (R = CN, CO2Et) provides the derivatives of the formula ( NC) RC = C (NEt2) CHFCl in approx. 70% yield The compounds of the formula (III) do not react with a, a-dihaloamines of the formula (II) in this condition.

Petrov et al. (J. of Fluorine Chem. (2011), 132 (12), 1198-1206) shows that TFEDMA (HCF2CF2NMe2) reacts with cyclic p-diketones to transfer a difluoroacetyl group.

In a preferred embodiment of the process according to the invention, the a, a-dihaloamine is reacted first with Lewis acid [L], for example, BF3, AlCl3, SbCl5, SbF5, ZnCh, and then the mixture of the compound of the formula (III) is added in substance or dissolved in an appropriate solvent (cf. WO 2008/022777).

a, a-Dihaloamines are reacted with Lewis acids (preparation of the iminium salts of the formula (V)) according to the training of WO 2008/022777. According to the invention, the reaction is carried out at

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temperatures from -20 ° C to + 40 ° C, preferably at temperatures from -20 ° C to + 30 ° C, more preferably from -10 to 20 ° C and under standard pressure. Due to the sensitivity of the hydrolysis of a, a-dihaloamines, the reaction is carried out in anhydrous apparatus under an inert gas atmosphere.

The reaction time is not critical and can, according to the batch size and temperature, be selected within a range of a few minutes to several hours.

According to the invention, 1 mole of the Lewis acid [L] is reacted with equimolar amounts of the a, dihaloamine of the formula (II).

For the process according to the invention 1 to 2 moles, preferred 1 to 1.5 mol, more preferred 1 to 1.2 mol of the a, a-dihaloamine of the formula (II) is reacted with the compound 1 mol of formula (III).

Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene , dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide or sulfones, such as sulfolane. Particular preference is given, for example, to THF, acetonitriles, ethers, toluene, xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, and very particular preference, for example, to acetonitrile, THF, ether or dichloromethane.

The intermediates of the formula (V) formed can be used in the cyclization step without prior treatment.

Especially the intermediates of the formula V-2 could easily be isolated from the reaction mixture in pure form after dilution with water. The isolated compounds of the formula V-2 are stable during storage and react with hydrazine of the formula IV producing the desired pyrazoles of the formula (I) in high and purity> 95-96%, to such an extent that no additional purification

Alternatively, the intermediates can be isolated by appropriate treatment steps, characterize and optionally further purified.

The compounds of formula (III) are partially new. They can be prepared from aldehydes or ketones (VII) according to the scheme shown below, see also Roeschenthaler et al, J. Fluorine.Chem. v. 125, n. 6, 1039-1049 and Tetrahedron, 69 (2013), 3878-3884.

Scheme 2:

image12

The reaction of the compound (VII) and (VI) according to the invention is carried out at temperatures of -40 ° C to + 120 ° C, preferably at temperatures of + 20 ° C to + 100 ° C, more preferably 20 ° C at + 60 ° C and under normal pressure.

For the process according to the invention 0.9 to 2 mol, preferred 1 to 1.8 mol, more preferred 1 to 1.2 mol of the compound of the formula (VI) is reacted with 1 mol of the compound of the formula (VII).

In case R is CF3, CF2H, CF2Cl and R is H it is preferable to use an excess of the compound of the formula (VII), 1.02 to 2 mol, preferably 1.01 to 1.8 mol, more preferably 1.01 to 1.2 mol , of the compound of the formula (VII) per 1 mol of the compound of the formula (VI).

The reaction time is not critical and can, according to the lot size and temperature, be selected within a range between a few and many hours.

Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene , dichloromethane, chloroform, tetrachloromethane, dichloroethane

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or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide or sulfones, such as sulfolane, alcohols such as methanol, ethanol, isopropanol butanol, esters such as ethyl and propylacetate. Particular preference is given to ethyl acetate, THF, acetonitriles, ethers, toluene, xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, ethanol and very particular preference to ethyl acetate, toluene, acetonitrile, THF, ether, dichloromethane, ethanol . The most preferred is toluene.

Stage (B)

According to the invention, 1 mol to 2 mol, preferably 1 to 1.5 mol of the hydrazine of the formula NH2-NHR4 for 1 mol of the compound of formula (V) is used.

Cyclization in step (B) of the compound of formula (V) is carried out at temperatures from -40 ° C to + 80 ° C, preferably at temperatures from + 20 ° C to + 70 ° C, more preferably from + 60 ° C and under standard pressure.

The reaction time is not critical and can, according to the lot size, be selected within a relatively wide range.

Generally, the step (B) of cyclization is performed without changing the solvent.

In general, the cyclization of the compound of the formula (V) proceeds in an acidic condition.

Preference is given to mineral acids, for example, H2SO4, HCl, HF, HBr, HI, H3PO4 or organic acids, for example, CH3COOH, CF3COOH, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid.

According to the invention, 0.1 mol to 2 mol, preferably 0.1 to 1.5 mol of the acid are used for 1 mol of the compound of formula (V).

Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example, petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene , dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane anisole; alcohols such as methanol, ethanol, isopropanol or butanol, nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide or sulfones, such as sulfolane, esters such as ethyl-, isopropyl- and propylacetate. Particular preference is given, for example, for isopropyl acetate, ethyl acetate, acetonitrile, toluene, xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, and very particular preference, for example, for ethyl acetate, acetonitrile, THF, toluene, isopropyl acetate or xylene. After the reaction is over, for example, the solvents were removed and the product was isolated by filtration or distillation, or a product solution was first washed with water, the organic phase was concentrated under reduced pressure.

The compounds of the formula (Ia / b) where R2 is COOR4 can be converted to pyrazole acid of the formula (I) being R2 COOH.

The amine (VI) can be reused for the preparation of compound (III). Alternatively, it is trapped by washing the reaction mixture with acid.

The compounds of the invention (Ia) and (Ib) are used for the preparation of fungicidal active ingredients. Preparation of the compound of formula (III):

N- (1,1-difluoropropan-2-ylidene) propan-2-amine, (III-1)

To the mixture of difluoracetone (94 g, 1 mol) in 500 mL of methyl tert-butyl ether, was added (88 g, 1.5 mol) of isopropylamine at 10 ° C. After 1 h, (70 g 0.5 mol) of BF3 * Et2O was added and the mixture was further stirred, for 1 h. The organic solution was separated from the syrup at the bottom and solvent was distilled off at atmospheric pressure. The remaining liquid was distilled in vacuo yielding 139 g of ketimine with a boiling point of 70-72 ° C / 400 mbar.

1 H NMR (601 MHz, CDCl 3): 8: 5.83 (t, 1 H), 3.74 (m, 1 H), 1.92 (s, 3 H), 1.15 (d, 6 H) ppm.

19F (566 MHz, CDCl3) 8-121.4 (d, 2F) ppm.

N-1,1-difluoropropan-2-ylidene-1-phenylmethanamine, (III-2).

To the mixture of difluoroacetone (94 g, 1 mol) in 500 mL of dichloromethane, slowly added (107 g, 1 mol) of benzylamine at 10 ° C. After 6 h at 20 ° C, CH2Cl2 was distilled off under reduced pressure and the remaining liquid was distilled under vacuum, yielding 161 g of ketimine with boiling point 80-82 ° C / 1.3 mbar.

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1H NMR (601 MHz, CDCI3) 8 7.36-7.26 (m, 5H), 5.94 (t, 1H), 4.55 (s, 2H), 2.03 (s, 3H) ppm.

19F (566 MHz, CDCI3) 8-121.2 (dt, 2F) ppm.

N- (1,1,1-trifluoropropan-2-ylidene) propan-2-amine, (MI-3) (see preparation of Example 2), boiling point 80-82 ° C.

N-1,1,1-trifluoropropan-2-ylidene-1-phenylmetanamin (III-4) (see preparation of Example 2) boiling point 90-91 ° C, 1.5 mbar.

Example 1 of the invention

3.5-bis (difluoromethyl) pyrazole, (I-1).

300 mL of acetonitrile were placed in a double jacketed flask and cooled to 0 ° C. AlCh 74.4 g (0.553 mol) was added portionwise at this temperature under intense stirring to form the yellow suspension. To this suspension, a solution of TFEDMA 80 g (0.553 mol) in 350 mL of acetonitrile was added at 10 ° C. The reaction mixture was stirred for 1 h at room temperature and solution of (53 g, 0.395 mol) of N-1,1 (- difluoropropan-2-ylidene) propan-2-amine was added within 1 h at 40 ° C and the mixture was stirred at this temperature, for 12 h. 100 mL of HCl (as a 5% solution in water) and 29 g of hydrazine hydrate were slowly added to the reaction solution to keep the temperature below 40 ° C and the mixture was stirred, for 5 h at 60 ° C forming two phases. The upper organic layer was separated, diluted with 500 mL of methyltertbutyl ether, washed twice with water, dried over MgSO4 and concentrated in vacuo to give an oily product. Vacuum distillation at 92-95 ° C / 1 mbar gave 56.4 g (85%) of pure 3,5-bis (difluoromethyl) -1H-pyrazole b) as a white solid with a melting point of 70-71 ° C.

1H NMR (601 MHz, CDCls) 8 11.93 (br, 1H), 6.88 (t, 2H, J = 54.8 Hz), 6.79 (s, 1H) ppm.

13C NMR (151 MHz, CDCN) 8 103.4 (p); 111.1 (t); 143.6 (br) ppm.

19 F NMR (566 Mhz), 8112.2 (d, br) ppm.

Example 2 of the invention

3.5-bis (difluoromethyl) pyrazole, (I-1).

BF3 (247 g 0.553 mol) as a 15% solution in CH3CN3 was placed in the flask and a solution of TFEDMA 80 g (0.553 mol) in 350 mL of acetonitrile was added at 10 ° C in portions at this temperature under intensive stirring. The reaction mixture was stirred for 1 h at room temperature and solution of (53 g, 0.395 mol) of N-1,1 (-difluoropropan-2-ylidene) propan-2-amine was added within 1 h at 40 ° C and the mixture was stirred at this temperature, for 12 h. 20 mL of HCl and 29 g of hydrazine hydrate were slowly added to the reaction mixture to keep the temperature below 40 ° C and the mixture was stirred, for 5 h at 60 ° C. The volatiles were removed in vacuo, 300 mL of methyltertbutyl ether was added to the residues and organic solution was washed twice with water, dried over MgSO4 and concentrated in vacuo to give an oily product. Vacuum distillation at 92-95 ° C / 1 mbar gave 58 g (87%) of pure 3,5-bis (difluoromethyl) -1H-pyrazole, as a white solid with melting point 70-71 ° C . 1H NMR (601 MHz, CDCla) 8 11.93 (br, 1H), 6.88 (t, 2H, J = 54.8 Hz), 6.79 (s, 1H).

Example 3 of the invention

3- (difluorometM) -5- (trifluorometM) -1H-pyrazole, (I-2).

30 mL of acetonitrile were placed in a double jacketed flask and cooled to 0 ° C. 4.8 g (0.055 mol) of BF3 * Et2O were added portionwise at this temperature under intensive stirring to form a yellow solution. A solution of TFEDMA 8 g (0.055 mol) in 35 mL of acetonitrile was added at 10 ° C. and the reaction mixture was stirred, for 1 h at room temperature. A solution of (5.3 g, 0.0395 mol) of N- (1,1,1-trifluoropropan-2-ylidene) propan-2-amine was added within 1 h at 40 ° C and the mixture was stirred at 40 ° C for 12 hours 15 mL of HCl (as a 5% solution in water) and 2.9 g of hydrazine hydrate were slowly added to the reaction solution to keep the temperature below 40 ° C and the The reaction mixture was stirred for 5 h at 60 ° C. Water (10 mL) was added and the solution was extracted with methyltertbutyleter (3 x 20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na 2 SO 4 and evaporated under reduced pressure The crude material was purified by column chromatography on silica gel with pentane / diethyl ether (100: 0 to 60:40) as eluent to provide the pure base compound (6.2 g, 85 %) as a pale yellow solid.

1H NMR (400 MHz, CDCh) 8 12.6 (br, 1H), 6.81 (s, 1H), 6.76 (t, 1H, J = 54.5 Hz); 13C (101 MHz, CDCh) 8 140.7, 128.8, 120.3 (q, Jc-f = 266 Hz), 108.5 (t, Jc-f = 237 Hz), 103.8; 19F (376 MHz, CDCh) 8 -61.7 (s, 3F), -112.9 (d, 2F, J = 54.7 Hz); HRMS (ESI) calculated for C5H4F5N2 [M + H] + 187.029, found 187.029.

Example 4 of the invention

3,5-bis (difluoromethyl) pyrazole, (I-1).

Stage A

(3 E / Z) -4- (benzylamino) -1,1,5,5-tetrafluoro-N, N-dimethylpent-3-en-2-iminium-tetrafluoroborate, (V-1-1).

5 BF3 (2.47 g 0.0553 mol) as a 15% solution in CH3CN3 was placed in the flask and a solution of TFEDMA 8 g (0.0553 mol) in 35 mL of acetonitrile was added at 10 ° C in portions at this temperature under intensive agitation. The reaction mixture was stirred for 1 h at room temperature and solution of (10.1 g, 0.0553 mol) of N-1,1-difluoropropan-2-ylidene-1-phenylmethanamine was added, within 1 h at 40 ° C and the mixture was stirred at this temperature, for 12 h. The solvent was removed under vacuum 2 mbar. The oily product was analyzed through NMR 10 spectroscopy showing the pure compound.

13C-NMR spectrum

13C NMR data were taken from HSQC and HMBC spectra. Data refer to CD3CN (1.3 ppm).

13C NMR (151 MHz, CD3CN) 8 164.8 (s, t), 159.5 (st); 135.1 (s); 129.6 (d), 129.0 (d), 128.4 (d); 110.6 (dt), 109.6 (dt), 86.7 (d); 49.2 (t); 46.1 (q, br); 43.7 (q, br) ppm.

15 1H NMR (601 MHz, CD3CN) 8 8.26 (br.s. 1H)), 7.42 (m, 2H), 7.37 (m, 3 H), 6.73 (t, 1H), 6.64 (t, 1H), 5.09 (s, br, 1H),

4.58 (s, br, 2H), 3.33 (s, br., 6H) ppm.

Stage B

An interaction of (3 E / Z) -4- (benzylamino) -1,1,5,5-tetrafluoro-N, N-dimethylpent-3-en-2-iminium tetrafluoroborate with N2H4 and HCl in Ethanol according to conditions in example 5 gave pure 3,5-bis (difluoromethyl) pyrazole with a yield of 89%.

Example 5 of the invention

Stage A

(4E- and 4Z) -benzylimino-1,1,5,5-tetrafluoro-pentan-2-one (V-2-1)

To a solution of 318 g of BF3 (as a 15.2% w / w solution in CH3CN), 107 g of

25 tetrafluoroethyldimethylamine from 0 to 5 ° C within 40 minutes. The pale yellow solution was stirred.

additionally, for 1 h at 0 ° C and the mixture was heated to 40 ° C within 1 h. 122.6 g of N-benzyl-1,1-difluoro-propan-2-imine were added at 40 ° C so fast to maintain the temperature in the reactor between 40-45 ° C (addition time 45 min). The reaction mixture was further stirred for 2 h at 40 ° C to give a pale yellow / clear solution. 200 mL of water was added with stirring to this solution at 0 ° C and after 10-15 30 min a white precipitate begins to form. The suspension was stirred, for 3-4 h at 0 ° C and the precipitate was filtered off, washed with 100 mL of water and dried at 40 ° C to give 152.2 g (yield 89%) of the product as a solid of White color with a melting point of 86-87 ° C.

Mixture of E / Z isomers in 25:75 ratio. 19F NMR (566 MHz, CD3CN, CFCh): E-isomer: -123.2 (d), -125.2 (d) ppm.

35 Z-Isomer: -120.8 (d), -125.9 (d)

1 H NMR (601 MHz, CD 3 CN): 25% E-isomer: 4.43, (d, 2 H); 5.42, (s, 1 H); 5.77, (t, 1 H); 7.32 (t, 1H), 7.33, (m, 2H); 7.42-7.32, m, (5H); 10.67 (s, br ,, 1H) ppm.

Isomer-Z 75%: 4.65, (d, 2H); 5.69, (s, 1 H); 5.92, (t, 1 H); 6.55 (t, 1H), 5.92 (t, 1H), 7.34, (m 2H), 7.42-7.32, (m, 5H); 10.67 (s, br, 1H) ppm.

40 Stage B

Partial amounts of the product obtained in step A were reacted with hydrazine hydrate (step B-1), N-methyl hydrazine (step B-2) and ethyl hydrazinoaetate hydrochloride (step B-3), respectively, to form the respective pyrazoles of formula (I-1), (I-3) and (I-4), respectively:

Stage B-1

45 3,5-bis (difluoromethyl) pyrazole (I-1)

2.4 g of hydrazine hydrate were added dropwise to the suspension of 10.4 g of (4E and 4Z) -benzylimino-1,1,5,5-tetrafluoro-pentan-2-one in 60 ml of acetate of ethyl. The mixture was stirred for 1 h at room temperature and then 15.6 g of 30% H2SO4 was added dropwise to the reaction mixture. The suspension was stirred for 2 h at 20 ° C, the precipitate was filtered and the organic phase was washed with water. The solvent was removed in vacuo to give 6.5 g 50 of the product with a melting point of 73-74 ° C.

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1H NMR (601 MHz, CDCI3) 5 12.5 (br, 1H), 6.77 (t, 2H, J 54.8 Hz), 6.74 (s, 1H).

Stage B-2

N-methyl-3,5-bis (difluoromethyl) pyrazole (I-3)

To a suspension of 2.6 g of (4E and 4Z) -benzylimino-1,1,5,5-tetrafluoro-pentan-2-one in 10 ml of ethanol was added 0.5 g of N-methylhydrazine at 20 ° C. The mixture was stirred for 1 h and then acidified by the addition of

3.6 g of 30% H2SO4. After 1 h the mixture was evaporated in vacuo and the product was extracted with methyl ether butyl ether. The organic phase was washed with water and concentrated in vacuo to give 1.7 g (94% yield) of oil product.

1 H NMR (601 MHz, CD 3 CN) 5 3.95 (s, 3 H), 6.77 (t, 1 H), 2 J = 54.7 Hz); 6.78 (s, 1 H); 6.95 (t, 1H, 2J = 53.4 Hz) ppm.

19F NMR (566 MHz, CD3CN, CFCl3) 5: -112.8 (d); 115.4 (d) ppm. m / z: 182.

Stage B-3

[3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] ethyl acetate (I-4)

To a suspension of 0.7 g of (4E and 4Z) -benzylimino-1,1,5,5-tetrafluoro-pentan-2-one in 20 ml of ethanol was added 0.45 g of ethyl hydrazinoacetate hydrochloride to 20 ° C The mixture was stirred for 10 h at 40 ° C and then acidified by adding 0.95 g of 30% H2SO4. After 1 h the mixture was evaporated in vacuo and the product was extracted with methyl ether butyl ether. The organic phase was washed with water and concentrated in vacuo to give

1.7 g (94% yield) of oil product.

1H NMR (601 MHz, CD3CN) 5: 1.24 (t, 3H), 4.20 (q, 2H), 5.07 (s, 2H) 6.79 (t, 1H, J = 54.7 Hz); 6.86 (s, 1 H); 6.94 (t, 1H,

J = 53.5 Hz) ppm.

19 F NMR (566 MHz, CD3CN) 5: -112.7 (d); -115.4 (d) ppm. m / z: 254

Preparation of intermediate compound (V-2-2):

(4E-y 4Z) -isopropylimino-1,1,5,5-tetrafluoro-pentan-2-one (V-2-2)

To a solution of 24.5 BF3 (as a 15.2% w / w solution in CH3CN) 8.2 g of tetrafluoroethyldimethylamine was added at 0 to 5 ° C within 40 minutes. The pale yellow solution was further stirred for 1 h at 0 ° C and the mixture was heated to 40 ° C within 1 h. 6.75 g of N-isopropyl-1,1-difluoro-propan-2-imine was added at 40 ° C so fast to maintain the temperature in a reactor between 40-45 ° C (addition time 45 min). The reaction mixture was further stirred for 2 h at 40 ° C to give a pale yellow / clear solution. 50 mL of water was added with stirring to this solution at 0 ° C and the two-phase mixture was stirred, for 1 h at 0 ° C and the product was extracted with ethyl acetate, the organic extract was washed with 100 mL of water and dried over MgSO4 to give 9.5 g (yield 89%) of the oil as a mixture of E / Z isomers in 83:17 ratio.

19F NMR (566 MHz, CD3CN): Z-isomer; -120.5 (d), -125.7 (d) ppm.

E-isomer: -123.1 (d), -125.0 (d) ppm.

1H NMR (601 MHz, CD3CN) E / Z isomers: 1.23, 1.27 (D, 6H); 3.72, 3.97 (M, 1H); 5.43, 5.57 (S, 1H); 5.85, 7.33, 5.90, 6.53 (T, 1H); 10.52 (S, br, 1H) ppm. m / z: 213.

Use of pyrazole (I-1) for the preparation of fungicides

2- {3- [2- (1 - {[3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] - 4,5-dihydro-1,2-oxazol-5-yl} -

3- chlorophenyl methanesulfonate

image13

16 g (0.03 mol) of 3-chloro-2- (3- {2- [1- (chloroacetyl) piperidin-4-yl] -1,3-thiazol-4-yl} -4,5-dihydro-1 , 2-oxazol-5-yl) phenyl methanesulfonate, 5.7 g (0.033 mol) 3,5-bis (difluoromethyl) -1H-pyrazole, 4.9 g (0.046 mol) sodium carbonate and 1.5 g

(0.005 mol) of tetrabutylammonium bromide are suspended in 100 mL of acetonitrile. The mixture is heated to 70 ° C and stirred, for 3.5 hours. At 40 ° C, most of the solvent is removed by vacuum filtration and replaced with 100 ml of toluene. The mixture was cooled to 20 ° C, stirred, for 1 hour, without seeds and then cooled to 5 ° C and stirred, for 1 hour. A mixture of 20 mL of water and 6 mL of 20% HCl is added and stirred for 30 minutes. The solid was filtered off, washed with toluene and water and dried at 45 ° C under vacuum.

18 g of 2- {3- [2- (1 - {[3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazole- are obtained 4-yl] -4,5-dihydro-1,2-oxazol-5-yl} -3-chlorophenyl methanesulfonate with a purity of 94% (yield: 84%).

Claims (9)

5 10 fifteen twenty 25 1. Preparation procedure for 3,5-bis (haloalkyl) pyrazoles of the formula (la) and (Ib) image 1 in which R and R are each independently selected from C1-C6 haloalkyl; R2 is selected from H, halogen, COOH, (C = O) OR5, CN and (C = O) NR6R7; R4 is selected from H, C1-C8 alkyl, CH2COO C1-C8 alkyl, aryl, pyridyl; R5 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl; R6 and R7 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl or in which R6 and R7 together with the nitrogen atom to which they bind can form a four, five or six member ring characterized in that in step (A), a, a-dihaloamines of the formula (II), image2 in which •one R is as defined above; X is independently selected from F, Cl or Br, R and R are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19 alkylaryl or wherein R10 and R11 together with the nitrogen atom to which they bind can form a five or six member ring; they are reacted with the compounds of the formula (III), image3 in which R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl and C7-C19- alkylaryl, OR9; R9 is selected from C1-C12 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, C7-C19 arylalkyl, C7-C19 alkylaryl; R2 and R3 are as defined above; to form the compound of formula (V): (V-1), (V-2), (V-3), (V-4) and (V-5) 5 10 fifteen twenty 25 30 35 40 image4 and ^ (V-2) v-n (V-3) (V-5) V-4 A- is BF4-. AICI3F ". AIF2CI2". AIF3CI- or ZnCl2F- R1, R2. R3, R5. Re, R7, Rs. RB, R10. R "are as defined above and because in step (B) in the presence of H2N-NHR4 hydrazine (IV) - R4 being as defined above - a cyclization of (V) is carried out to form (la / Ib). 2. Method according to claim 1, characterized in that R1 and R3 are each independently selected from difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2 -difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, tetrafluoroethyl (CF3CFH), pentafluoroethyl and 1,1,1-trifluoroprop-2-yl; R2 is selected from H, F, Cl, Br, COOCH3, COOC2H5, COOC3H7, CN and CON (CH3) 2, CON ^ Hsfe R4 is selected from H, CrC8-alkyl, CH2COOC1-C8-alkyl, phenyl, pyridyl; R8 * are each independently selected from methyl, ethyl, n-, / so-propyl, n-, iso-, sec- and f-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, C7- alkylaryl C19, tolyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl; X is independently selected from F or Cl; R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C7-C19 or R10 and R11 arylalkyl together with the nitrogen atom to which they are attached can form a five-membered ring. 3. Method according to claim 1, characterized in that R1 and R3 are each independently selected from trifluoromethyl, difluoromethyl, difluorochloromethyl, pentafluoroethyl; R2 is selected from H, Cl, CN, COOC2H5; R4 is selected from H, methyl, ethyl, n-, isopropyl, n-, iso-, sec- and f-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, phenyl, CH2COOCH3, CH2COOCH2CH3; R8 is selected from methyl, ethyl, n-, / so-propyl, n-, iso-, sec- and f-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, C7-C19 alkylaryl; X is independently selected from F or Cl; R10 and R11 are each independently selected from C1-C12 alkyl, C3-C8 cycloalkyl. 4. Method according to claim 1, characterized in that R1 and R3 are each independently selected from CF2H and CF3; R2 is selected from H or COOC2H5; R4 is selected from H, methyl, ethyl, CH2COOCH3, CH2COOCH2CH3, phenyl; R8 is selected from ethyl, n-, / so-propyl, n-, cyclopentyl, cyclohexyl, benzyl; X is F; R10 and R11 are each independently selected from C1-C12 alkyl. 5. Method according to claim 1, characterized in that R1 and R3 are CF2H ;; R2 is H; R4 is selected from H, methyl, CH2COOCH2CH3, phenyl; R8 is selected from / so-propyl and benzyl; X is F; R10 and R11 are each independently selected from methyl and ethyl. 5 10 fifteen 6. Compounds of formula (V-1) in which image5 R1 and R3 are HCF2; R2 is H; R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl and benzyl; R10 and R11 are each independently selected from C1-C5 alkyl; A is BF4 ". 7. Compounds of formula (V-2) image6 in which R1 and R3 are HCF2; R2 is H; R8 is selected from C1-C12 alkyl, C3-C8 cycloalkyl and benzyl. 8. Compounds of formula (V-3) in which image7 R1 and R3 are HCF2; R2 is H; R8 is selected from C1-12 alkyl, C3-8 cycloalkyl and benzyl; R10 and R11 are each independently selected from C ^ alkyl. 9. Compounds of formula (V-4) image8 in which R1 and R3 are HCF2; 5 R2 is H; R8 is selected from C1.12 alkyl, C3-8 cycloalkyl and benzyl.